GIANCARLO MARI

Current Diagnosis and Management of Red-Cell

Alloimmunization

11

Congress of Maternal Fetal Medicine and Perinatology Society of Turkey

Giancarlo Mari, MD, MBA, FACOG, FAIUM Professor and Chair

Dept. of Obstetrics and Gynecology UTHSC, Memphis, TN

At the end of this presentation the participants will be able

• To Describe

– The Rh alloimmunization story

– The role of Doppler ultrasound of the middle cerebral artery in fetal anemia

– The standard of care for the diagnosis and

management of fetal anemia

Definition of fetal anemia

Hemoglobin value below the 5 ^th percentile (2 SD; 95% CI)

for gestational age

Causes of fetal anemia

• Red blood cell alloimmunization

• Infections

• Fetomaternal hemorrhage

• Twin-twin-transfusion syndrome

• Thalassemia

• Enzymopathies

• Fanconi anemia

• Diamond-Blackfan anemia

Before 1968

>10,000 deaths in the USA for HDN

Rh hemolytic disease United States

~ ??? cases per year

Rhogam (1968)

“Irregular” red blood cell antigens

Blood group system Antigen

Rh C, c, e, E

Kell K, k, Ko, Kp^a, Kp^b, Js^a, Js^b Duffy Fy^a, Fy^b, Fy³

Kidd Jk^a, Jk^b, Jk³

MNSs M, N, S, s, U, Mi^a, Mt^a, Vw, Mur, Hil, Hut

Lutheran Lua, Lub

Diego Dia, Dib

Xg Xga

P PP₁p^k(Tj^a)

Public antigens Yt^a, Yt^b, Lan, En^a, Ge, Jr^a, Co^a, Co^a-b- Private antigens Batty, Becker, Berrens, Biles, Evans,

Gonzales, Good, Heibel, Hunt, Jobbins, Radin, Rm, Ven, Wright^a, Wright^b, Zd

Karl Landsteiner

Nobel prize in Physiology/Medicine (1930) for

his discovery of human blood groups (1901)

Philip Levine, MD

RH and Fetal hemolytic disease (1937-1941)

K. Landsteiner - A,B,O phenotypes: 1901 K. Landsteiner and Wiener - anti-Rh: 1940 P. Levine - anti Rh cause of HDN: 1941 D. Bevis - Amniocentesis in HDN: 1953

Rh – Medical Discoveries

Albert William Liley

DeltaOD450 (1961)

Rh-Cell Alloimmunization:

The Story

Freda V, Am J Obstet Gynecol 1964;89:817-21

Vincent Freda and John O. Gorman (1968)

Rhogam

Cyril A. Clarke Ronald Finn

Lasker award in 1980

William Pollack

Vincent J. Freda John G. Gorman

Fetoscopy

A) Diagnosis of open spina bifida B) Fetal blood sampling

Valenti C. Am J Obstet Gynecol 1973;11:581

Fernand Daffos

Cordocentesis (1983)

Cord blood sampling

Daffos F, et al. Am J Obstet Gynecol 1983;146:985

Amniocentesis Cordocentesis

Fetal Anemia

24 wks

1

2 3

4

5 6

Mari

Blood velocity in anemia

Viscosity CO

Velocity

Christian J. Doppler was an

Austrian physicist who described the Doppler effect in 1842.

Fd = 2(Fc x V x cos α) C

Doppler Formula

Mari

Angle Dependence

Mari

Middle Cerebral Artery Peak

Systolic Velocity

C B A

D

Where to sample the MCA?

A

C

It is easy to sample the MCA with an angle of zero degrees, which allows for the real

velocity of the blood flow to be determined.

These are the steps for the correct sampling of the middle cerebral

artery peak systolic velocity.

The use of an angle corrector increases the intra- and inter-observer variability; therefore, its use is not recommended.

B

D

E F

Ultrasound Obstet Gynecol 1995;5:400

Ultrasound Obstet Gynecol 1995;5:400

Gestational Age (weeks)

16 18 20 22 24 26 28 30 32 34 36

Hemoglobin (gr/dl)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

95

50

5

Moderate Anemia Severe Anemia

Severe Anemia with risk of Hydrops Mild Anemia

N Engl J Med. 2000;342(1):9-14

N Engl J Med. 2000;342(1):9-14

Mari G, et al N Engl J Med 2000; 342:9

1.5 MoM

Prospective study on an intention to treat

• Multicenter study in 5 tertiary referral centers

• 125 fetuses at risk for anemia

• MCA-PSV used for timing a cordocentesis

Zimmermann R, et al. Br J Obstet Gynaecol 2002;109:746

False Positive Rate

• MCA PSV single value: False positive rate: 12%

• MCA PSV trend: False positive rate: <5%

N Engl J Med 2000; 342:9

Zimmermann R, et al. Br J Obstet Gynaecol 2002;109:746

N Engl J Med 2006;355:156

All Truth Passes Through Three Stages:

•

• Second It is Violently Opposed

• Third It is Accepted As Being Self-Evident

A. Schopenhauer

Management of Alloimmunization

Argoti P, et al. Minerva Ginecologica, in press

Intrauterine transfusion

Overall rate of complications of 3.3% per fetus and 1.2% per procedure

A fetal loss rate of 17% when the fetal blood sampling is performed at < 20 weeks.

Zwiers C, et al. Ultrasound Obstet Gynecol. 2017;50(2):180-6

Intrauterine transfusion

• VOLUME TO TRASFUSE INTRAVASCULARLY = (Desired hematocrit-Fetal hematocrit/Donor hematocrit-desired hematocrit) x Fetoplacental volume

• VOLUME TO TRANSFUSE INTRAPERITONEALLY = (GA in weeks – 20 ) x 10

Transfusion Intervals

• The MCA-PSV hold its negative predictive value and may be factored when planning subsequent IUT intervals

• A recent randomized trial, that compared timing of

subsequent transfusions with the use of the MCA-PSV (serial upward trend of values > 1.5 MoM) vs. expected decrease in fetal hematocrit found no differences in mean hemoglobin levels at birth, number of IUT procedures or in the rates of adverse infant outcomes

Dodd JM, et al. Ultrasound Obstet Gynecol. 2018;51(3):306-12

Immunoglobulin

Zwiers C, et al. Am J Obstet Gynecol. 2018;219(3):291 e1- e9

PETIT study: retrospective study in 12 fetal therapy centers, of early onset, (<13 weeks of gestation) intrauterine

immunoglobulin treatment, of pregnancies previously affected by severe hemolytic disease of the fetus and newborn (HDFN)

Results suggested that IG therapy may delay the onset of severe anemia and may decrease the incidence of hydrops and the need of newborn exchange transfusion

Is the MCA-PSV reliable for the diagnosis of fetal anemia due to

other causes?

Which patients are candidates for the assessment of the MCA-PSV?

• Patients at risk for having an anemic fetus

• Indiscrimate use of the MCA-PSV may cause more

harm than good

Conclusion

RH story

• A successful story in Fetal Medicine

• Mirror of what is happening in Fetal Medicine

First “Do no harm”

Case 1 History

• Rising delta OD

in amniotic fluid

• 33 yo, G3 P0 Rh sensitized (anti D = 1/64)

• Fetus is Rh positive

Delta OD ₄₅₀

20 25 30 35

Gestational age (weeks)

0.02 0.50

0.10

●

●

Low

Intermediate

Severe

Extremely High

Case 1 History

• Referred at 22.1 weeks’ gestation

• Cordocentesis at 22 weeks (unsuccessful)

• Rising delta OD

in amniotic fluid

• 33 yo, G3 P0 Rh sensitized (anti D = 1/64)

• Fetus is Rh positive

Anti D = 1/256 Middle Cerebral Artery Peak Systolic Velocity

Gestational Age (wks)

Median 1.5MoM

●

● ●

Hgb = 5.5 g/dL

● MCA-PSV 70cm/S

Hgb = 7.4 g/dL

● 50cm/s

●

32cm/s

●

●

●

Hgb = 9.0 g/dL

Gestational Age (weeks)

18 20 22 24 26 28 30 32 34 36 38 40

Hemoglobin (gr/dl)

4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Severe Anemia Moderate Anemia Mild Anemia

95

50

5

Is the delta OD ₄₅₀ better than MCA-PSV or vice versa?

• Am J Obstet Gynecol 1997 (SMFM);180:18

• Pereira L, et al. Am J Obstet Gynecol 2003;189:1002-6

• Oepkes D, et al Am J Obstet Gynecol 2004 (SMFM);194:3